Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.
Arrhythmia
Cardiac
Cardiology
Companion animal
Complex trait
GWAS
Genetics
Transcriptomics
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
18 09 2023
18 09 2023
Historique:
received:
09
03
2023
accepted:
17
08
2023
medline:
20
9
2023
pubmed:
19
9
2023
entrez:
18
9
2023
Statut:
epublish
Résumé
Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis. We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts. Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes. Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.
Sections du résumé
BACKGROUND
Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.
METHODS
We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts.
RESULTS
Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes.
CONCLUSIONS
Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.
Identifiants
pubmed: 37723491
doi: 10.1186/s13073-023-01221-3
pii: 10.1186/s13073-023-01221-3
pmc: PMC10506233
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
73Subventions
Organisme : Department of Health
Pays : United Kingdom
Investigateurs
Carsten Daub
(C)
César L Araujo
(CL)
Ileana B Quintero
(IB)
Kaisa Kyöstilä
(K)
Maria Kaukonen
(M)
Meharji Arumilli
(M)
Riika Sarviaho
(R)
Jenni Puurunen
(J)
Sini Sulkama
(S)
Sini Karjalainen
(S)
Antti Sukura
(A)
Pernilla Syrjä
(P)
Niina Airas
(N)
Henna Pekkarinen
(H)
Ilona Kareinen
(I)
Hanna-Maaria Javela
(HM)
Anna Knuuttila
(A)
Heli Nordgren
(H)
Karoliina Hagner
(K)
Tarja Pääkkönen
(T)
Antti Iivanainen
(A)
Kaarel Krjutskov
(K)
Sini Ezer
(S)
Auli Saarinen
(A)
Shintaro Katayama
(S)
Masahito Yoshihara
(M)
Abdul Kadir Mukarram
(AK)
Rasha Fahad Aljelaify
(RF)
Fiona Ross
(F)
Amitha Raman
(A)
Irene Stevens
(I)
Oleg Gusev
(O)
Danika Bannasch
(D)
Jeffrey J Schoenebeck
(JJ)
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
McNally EM, Mestroni L. Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res. 2017;121:731–48. https://doi.org/10.1161/CIRCRESAHA.116.309396 .
doi: 10.1161/CIRCRESAHA.116.309396
pubmed: 28912180
pmcid: 5626020
Jordan E, et al. Evidence-based assessment of genes in dilated cardiomyopathy. Circulation. 2021;144:7–19. https://doi.org/10.1161/CIRCULATIONAHA.120.053033 .
doi: 10.1161/CIRCULATIONAHA.120.053033
pubmed: 33947203
pmcid: 8247549
Tayal U, Prasad S, Cook SA. Genetics and genomics of dilated cardiomyopathy and systolic heart failure. Genome Med. 2017;9:20. https://doi.org/10.1186/s13073-017-0410-8 .
doi: 10.1186/s13073-017-0410-8
pubmed: 28228157
pmcid: 5322656
Esslinger U, et al. Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS One. 2017;12:e0172995. https://doi.org/10.1371/journal.pone.0172995 .
doi: 10.1371/journal.pone.0172995
pubmed: 28296976
pmcid: 5351854
Aragam KG, et al. Phenotypic refinement of heart failure in a national biobank facilitates genetic discovery. Circulation. 2018. https://doi.org/10.1161/CIRCULATIONAHA.118.035774 .
doi: 10.1161/CIRCULATIONAHA.118.035774
pubmed: 30586722
pmcid: 6511334
Garnier S, et al. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. Eur Heart J. 2021;42:2000–11. https://doi.org/10.1093/eurheartj/ehab030 .
doi: 10.1093/eurheartj/ehab030
pubmed: 33677556
pmcid: 8139853
Egenvall A, Bonnett BN, Haggstrom J. Heart disease as a cause of death in insured Swedish dogs younger than 10 years of age. J Vet Intern Med. 2006;20:894–903. https://doi.org/10.1892/0891-6640(2006)20[894:hdaaco]2.0.co;2 .
doi: 10.1892/0891-6640(2006)20[894:hdaaco]2.0.co;2
pubmed: 16955814
Stern JA, Ueda Y. Inherited cardiomyopathies in veterinary medicine. Pflugers Arch. 2019;471:745–53. https://doi.org/10.1007/s00424-018-2209-x .
doi: 10.1007/s00424-018-2209-x
pubmed: 30284024
Lewis TW, Wiles BM, Llewellyn-Zaidi AM, Evans KM, O’Neill DG. Longevity and mortality in Kennel Club registered dog breeds in the UK in 2014. Canine Genet Epidemiol. 2018;5:10. https://doi.org/10.1186/s40575-018-0066-8 .
doi: 10.1186/s40575-018-0066-8
pubmed: 30349728
pmcid: 6191922
Tidholm A, Haggstrom J, Borgarelli M, Tarducci A. Canine idiopathic dilated cardiomyopathy. Part I: aetiology, clinical characteristics, epidemiology and pathology. Vet J. 2001;162:92–107. https://doi.org/10.1053/tvjl.2001.0571 .
doi: 10.1053/tvjl.2001.0571
pubmed: 11531394
Broschk C, Distl O. Dilated cardiomyopathy (DCM) in dogs–pathological, clinical, diagnosis and genetic aspects. Dtsch Tierarztl Wochenschr. 2005;112:380–5.
pubmed: 16320572
Simpson S, et al. Genetics of human and canine dilated cardiomyopathy. Int J Genomics. 2015;2015:204823. https://doi.org/10.1155/2015/204823 .
doi: 10.1155/2015/204823
pubmed: 26266250
pmcid: 4525455
Gaar-Humphreys KR, et al. Genetic basis of dilated cardiomyopathy in dogs and its potential as a bidirectional model. Animals (Basel). 2022;12(13):1679. https://doi.org/10.3390/ani12131679 .
doi: 10.3390/ani12131679
pubmed: 35804579
Smucker ML, et al. Naturally occurring cardiomyopathy in the Doberman pinscher: a possible large animal model of human cardiomyopathy? J Am Coll Cardiol. 1990;16:200–6. https://doi.org/10.1016/0735-1097(90)90480-d .
doi: 10.1016/0735-1097(90)90480-d
pubmed: 2358594
Lee BH, Dukes-McEwan J, French AT, Corcoran BM. Evaluation of a novel Doppler index of combined systolic and diastolic myocardial performance in Newfoundland dogs with familial prevalence of dilated cardiomyopathy. Vet Radiol Ultrasound. 2002;43:154–65. https://doi.org/10.1111/j.1740-8261.2002.tb01663.x .
doi: 10.1111/j.1740-8261.2002.tb01663.x
pubmed: 11954811
Meurs KM, Miller MW, Wright NA. Clinical features of dilated cardiomyopathy in Great Danes and results of a pedigree analysis: 17 cases (1990–2000). J Am Vet Med Assoc. 2001;218:729–32. https://doi.org/10.2460/javma.2001.218.729 .
doi: 10.2460/javma.2001.218.729
pubmed: 11280406
Philipp U, Vollmar A, Haggstrom J, Thomas A, Distl O. Multiple loci are associated with dilated cardiomyopathy in Irish wolfhounds. PLoS One. 2012;7:e36691. https://doi.org/10.1371/journal.pone.0036691 .
doi: 10.1371/journal.pone.0036691
pubmed: 22761652
pmcid: 3382626
Wess G, et al. Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups. J Vet Intern Med. 2010;24:533–8. https://doi.org/10.1111/j.1939-1676.2010.0479.x .
doi: 10.1111/j.1939-1676.2010.0479.x
pubmed: 20202106
Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10:531–47. https://doi.org/10.1038/nrcardio.2013.105 .
doi: 10.1038/nrcardio.2013.105
pubmed: 23900355
Weintraub RG, Semsarian C, Macdonald P. Dilated cardiomyopathy. Lancet. 2017;390:400–14. https://doi.org/10.1016/S0140-6736(16)31713-5 .
doi: 10.1016/S0140-6736(16)31713-5
pubmed: 28190577
Wess G, Domenech O, Dukes-McEwan J, Haggstrom J, Gordon S. European Society of Veterinary Cardiology screening guidelines for dilated cardiomyopathy in Doberman Pinschers. J Vet Cardiol. 2017;19:405–15. https://doi.org/10.1016/j.jvc.2017.08.006 .
doi: 10.1016/j.jvc.2017.08.006
pubmed: 28965673
van Steenbeek FG, Hytonen MK, Leegwater PA, Lohi H. The canine era: the rise of a biomedical model. Anim Genet. 2016;47:519–27. https://doi.org/10.1111/age.12460 .
doi: 10.1111/age.12460
pubmed: 27324307
Axelsson E, et al. The genetic consequences of dog breed formation-accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels. PLoS Genet. 2021;17:e1009726. https://doi.org/10.1371/journal.pgen.1009726 .
doi: 10.1371/journal.pgen.1009726
pubmed: 34473707
pmcid: 8412370
Lindblad-Toh K, et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature. 2005;438:803–19.
doi: 10.1038/nature04338
pubmed: 16341006
van der Velden J, et al. Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart. Cardiovasc Res. 2022;118:3016–51. https://doi.org/10.1093/cvr/cvab370 .
doi: 10.1093/cvr/cvab370
pubmed: 34999816
pmcid: 9732557
Sutter NB, et al. Extensive and breed-specific linkage disequilibrium in Canis familiaris. Genome Res. 2004;14:2388–96. https://doi.org/10.1101/gr.3147604 .
doi: 10.1101/gr.3147604
pubmed: 15545498
pmcid: 534662
Hytonen MK, et al. Molecular characterization of three canine models of human rare bone diseases: Caffey, van den Ende-Gupta, and Raine syndromes. PLoS Genet. 2016;12:e1006037. https://doi.org/10.1371/journal.pgen.1006037 .
doi: 10.1371/journal.pgen.1006037
pubmed: 27187611
pmcid: 4871343
Holopainen S, et al. ANLN truncation causes a familial fatal acute respiratory distress syndrome in Dalmatian dogs. PLoS Genet. 2017;13:e1006625. https://doi.org/10.1371/journal.pgen.1006625 .
doi: 10.1371/journal.pgen.1006625
pubmed: 28222102
pmcid: 5340406
Wielaender F, et al. Generalized myoclonic epilepsy with photosensitivity in juvenile dogs caused by a defective DIRAS family GTPase 1. Proc Natl Acad Sci U S A. 2017;114:2669–74. https://doi.org/10.1073/pnas.1614478114 .
doi: 10.1073/pnas.1614478114
pubmed: 28223533
pmcid: 5347561
Kyostila K, et al. Intronic variant in POU1F1 associated with canine pituitary dwarfism. Hum Genet. 2021;140:1553–62. https://doi.org/10.1007/s00439-021-02259-2 .
doi: 10.1007/s00439-021-02259-2
pubmed: 33550451
pmcid: 8519942
Mandigers PJJ, Van Steenbeek FG, Bergmann W, Vos-Loohuis M, Leegwater PA. A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy. Hum Genet. 2021;140:1547–52. https://doi.org/10.1007/s00439-021-02271-6 .
doi: 10.1007/s00439-021-02271-6
pubmed: 33677640
pmcid: 8519843
Meurs KM, et al. Evaluation of the cardiac actin gene in Doberman Pinschers with dilated cardiomyopathy. Am J Vet Res. 2001;62:33–6. https://doi.org/10.2460/ajvr.2001.62.33 .
doi: 10.2460/ajvr.2001.62.33
pubmed: 11197556
Stabej P, Leegwater PA, Stokhof AA, Domanjko-Petric A, van Oost BA. Evaluation of the phospholamban gene in purebred large-breed dogs with dilated cardiomyopathy. Am J Vet Res. 2005;66:432–6. https://doi.org/10.2460/ajvr.2005.66.432 .
doi: 10.2460/ajvr.2005.66.432
pubmed: 15822587
Meurs KM, Hendrix KP, Norgard MM. Molecular evaluation of five cardiac genes in Doberman Pinschers with dilated cardiomyopathy. Am J Vet Res. 2008;69:1050–3. https://doi.org/10.2460/ajvr.69.8.1050 .
doi: 10.2460/ajvr.69.8.1050
pubmed: 18672969
Mausberg TB, et al. A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers. PLoS One. 2011;6:e20042. https://doi.org/10.1371/journal.pone.0020042 .
doi: 10.1371/journal.pone.0020042
pubmed: 21625443
pmcid: 3098859
Owczarek-Lipska M, et al. A 16-bp deletion in the canine PDK4 gene is not associated with dilated cardiomyopathy in a European cohort of Doberman Pinschers. Anim Genet. 2013;44:239. https://doi.org/10.1111/j.1365-2052.2012.02396.x .
doi: 10.1111/j.1365-2052.2012.02396.x
pubmed: 22834541
O’Sullivan ML, O’Grady MR, Pyle WG, Dawson JF. Evaluation of 10 genes encoding cardiac proteins in Doberman Pinschers with dilated cardiomyopathy. Am J Vet Res. 2011;72:932–9. https://doi.org/10.2460/ajvr.72.7.932 .
doi: 10.2460/ajvr.72.7.932
pubmed: 21728854
Meurs KM, et al. A missense variant in the titin gene in Doberman Pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death. Hum Genet. 2019;138:515–24. https://doi.org/10.1007/s00439-019-01973-2 .
doi: 10.1007/s00439-019-01973-2
pubmed: 30715562
Meurs KM, et al. A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman Pinscher. Hum Genet. 2012;131:1319–25. https://doi.org/10.1007/s00439-012-1158-2 .
doi: 10.1007/s00439-012-1158-2
pubmed: 22447147
Meurs KM, et al. Assessment of PDK4 and TTN gene variants in 48 Doberman Pinschers with dilated cardiomyopathy. J Am Vet Med Assoc. 2020;257:1041–4. https://doi.org/10.2460/javma.2020.257.10.1041 .
doi: 10.2460/javma.2020.257.10.1041
pubmed: 33135971
Wess G. Screening for dilated cardiomyopathy in dogs. J Vet Cardiol. 2022;40:51–68. https://doi.org/10.1016/j.jvc.2021.09.004 .
doi: 10.1016/j.jvc.2021.09.004
pubmed: 34732313
Wess G, Maurer J, Simak J, Hartmann K. Use of Simpson’s method of disc to detect early echocardiographic changes in Doberman Pinschers with dilated cardiomyopathy. J Vet Intern Med. 2010;24:1069–76. https://doi.org/10.1111/j.1939-1676.2010.0575.x .
doi: 10.1111/j.1939-1676.2010.0575.x
pubmed: 20707842
Geraghty N, Wess G. Vergleich verschiedener Holterkriterien zur Diagnose des arrhythmischen Stadiums der dilatativen Kardiomyopathie beim Dobermann. Munich: Tieraerztliche Fakultaet der LMU Munich; 2011.
Eberhard J, Wess G. The prevalence of atrial premature complexes in healthy Doberman Pinschers and their role in the diagnosis of occult dilated cardiomyopathy. Vet J. 2020;259–260:105475. https://doi.org/10.1016/j.tvjl.2020.105475 .
doi: 10.1016/j.tvjl.2020.105475
pubmed: 32553239
Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.
doi: 10.1086/519795
pubmed: 17701901
pmcid: 1950838
Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012;44:821–4. https://doi.org/10.1038/ng.2310 .
doi: 10.1038/ng.2310
pubmed: 22706312
pmcid: 3386377
Gao X. Multiple testing corrections for imputed SNPs. Genet Epidemiol. 2011;35:154–8. https://doi.org/10.1002/gepi.20563 .
doi: 10.1002/gepi.20563
pubmed: 21254223
pmcid: 3055936
Gao X, Becker LC, Becker DM, Starmer JD, Province MA. Avoiding the high Bonferroni penalty in genome-wide association studies. Genet Epidemiol. 2010;34:100–5. https://doi.org/10.1002/gepi.20430 .
doi: 10.1002/gepi.20430
pubmed: 19434714
pmcid: 2796708
Gao X, Starmer J, Martin ER. A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet Epidemiol. 2008;32:361–9. https://doi.org/10.1002/gepi.20310 .
doi: 10.1002/gepi.20310
pubmed: 18271029
Robinson D, Hayes A, Couch S. broom: Convert Statistical Objects into Tidy Tibbles. 2023. https://broom.tidymodels.org/ , https://github.com/tidymodels/broom .
Wickham H, François R, Henry L, Müller K, Vaughan D. dplyr: A Grammar of Data Manipulation. 2023. https://dplyr.tidyverse.org , https://github.com/tidyverse/dplyr .
Wickham H. ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York; 2016. ISBN 978-3-319-24277-4, https://ggplot2.tidyverse.org .
Fox J, Weisberg S. An R Companion to Applied Regression, Third edition. Thousand Oaks: Sage; 2019. https://socialsciences.mcmaster.ca/jfox/Books/Companion/ .
Lenth RV. emmeans: estimated marginal means, aka least-squares means. J Stat Softw. 2016;69:1–33. https://doi.org/10.18637/jss.v069.i01 .
doi: 10.18637/jss.v069.i01
R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2021. https://www.R-project.org/ .
Jagannathan V, Drogemuller C, Leeb T, Dog Biomedical Variant Database C. A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves. Anim Genet. 2019;50:695–704. https://doi.org/10.1111/age.12834 .
doi: 10.1111/age.12834
pubmed: 31486122
pmcid: 6842318
Hytonen MK, Lohi H. A frameshift insertion in SGK3 leads to recessive hairlessness in Scottish Deerhounds: a candidate gene for human alopecia conditions. Hum Genet. 2019;138:535–9. https://doi.org/10.1007/s00439-019-02005-9 .
doi: 10.1007/s00439-019-02005-9
pubmed: 30927068
pmcid: 6536473
Dillard KJ, et al. Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs. PLoS Genet. 2020;16:e1008651. https://doi.org/10.1371/journal.pgen.1008651 .
doi: 10.1371/journal.pgen.1008651
pubmed: 32150563
pmcid: 7082050
Ashburner M, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–9. https://doi.org/10.1038/75556 .
doi: 10.1038/75556
pubmed: 10802651
pmcid: 3037419
The Gene Ontology C. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. 2019;47:D330–8. https://doi.org/10.1093/nar/gky1055 .
doi: 10.1093/nar/gky1055
Bult CJ, et al. Mouse Genome Database (MGD) 2019. Nucleic Acids Res. 2019;47:D801–6. https://doi.org/10.1093/nar/gky1056 .
doi: 10.1093/nar/gky1056
pubmed: 30407599
Uhlen M, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419. https://doi.org/10.1126/science.1260419 .
doi: 10.1126/science.1260419
pubmed: 25613900
Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4. https://doi.org/10.1093/nar/gkg509 .
doi: 10.1093/nar/gkg509
pubmed: 12824425
pmcid: 168916
Koressaar T, Remm M. Enhancements and modifications of primer design program Primer3. Bioinformatics. 2007;23:1289–91. https://doi.org/10.1093/bioinformatics/btm091 .
doi: 10.1093/bioinformatics/btm091
pubmed: 17379693
Okonechnikov K, Golosova O, Fursov M, team U. Unipro UGENE: a unified bioinformatics toolkit. Bioinformatics. 2012;28:1166–7. https://doi.org/10.1093/bioinformatics/bts091 .
doi: 10.1093/bioinformatics/bts091
pubmed: 22368248
Cheng Y, Hogarth KA, O’Sullivan ML, Regnier M, Pyle WG. 2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2016;310:H80–91. https://doi.org/10.1152/ajpheart.00530.2015 .
doi: 10.1152/ajpheart.00530.2015
pubmed: 26497964
Tsimakouridze EV, et al. Chronomics of pressure overload-induced cardiac hypertrophy in mice reveals altered day/night gene expression and biomarkers of heart disease. Chronobiol Int. 2012;29:810–21. https://doi.org/10.3109/07420528.2012.691145 .
doi: 10.3109/07420528.2012.691145
pubmed: 22823865
Andrews S. FastQC: A Quality Control Tool for High Throughput Sequence Data [Online]. 2010. Available online at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/ .
Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20. https://doi.org/10.1093/bioinformatics/btu170 .
doi: 10.1093/bioinformatics/btu170
pubmed: 24695404
pmcid: 4103590
Kopylova E, Noe L, Touzet H. SortMeRNA: fast and accurate filtering of ribosomal RNAs in metatranscriptomic data. Bioinformatics. 2012;28:3211–7. https://doi.org/10.1093/bioinformatics/bts611 .
doi: 10.1093/bioinformatics/bts611
pubmed: 23071270
Dobin A, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21. https://doi.org/10.1093/bioinformatics/bts635 .
doi: 10.1093/bioinformatics/bts635
pubmed: 23104886
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30. https://doi.org/10.1093/bioinformatics/btt656 .
doi: 10.1093/bioinformatics/btt656
pubmed: 24227677
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40. https://doi.org/10.1093/bioinformatics/btp616 .
doi: 10.1093/bioinformatics/btp616
pubmed: 19910308
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. https://doi.org/10.1186/s13059-014-0550-8 .
doi: 10.1186/s13059-014-0550-8
pubmed: 25516281
pmcid: 4302049
Robinson JT, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6. https://doi.org/10.1038/nbt.1754 .
doi: 10.1038/nbt.1754
pubmed: 21221095
pmcid: 3346182
Hoeppner MP, et al. An improved canine genome and a comprehensive catalogue of coding genes and non-coding transcripts. PLoS One. 2014;9:e91172. https://doi.org/10.1371/journal.pone.0091172 .
doi: 10.1371/journal.pone.0091172
pubmed: 24625832
pmcid: 3953330
Kent WJ. BLAT–the BLAST-like alignment tool. Genome Res. 2002;12:656–64. https://doi.org/10.1101/gr.229202 .
doi: 10.1101/gr.229202
pubmed: 11932250
pmcid: 187518
Benson DA, et al. GenBank. Nucleic Acids Res. 2018;46:D41–7. https://doi.org/10.1093/nar/gkx1094 .
doi: 10.1093/nar/gkx1094
pubmed: 29140468
Andersson R, et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014;507:455–61. https://doi.org/10.1038/nature12787 .
doi: 10.1038/nature12787
pubmed: 24670763
pmcid: 5215096
Karczewski KJ, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43. https://doi.org/10.1038/s41586-020-2308-7 .
doi: 10.1038/s41586-020-2308-7
pubmed: 32461654
pmcid: 7334197
Adzhubei IA, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9. https://doi.org/10.1038/nmeth0410-248 .
doi: 10.1038/nmeth0410-248
pubmed: 20354512
pmcid: 2855889
Bycroft C, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203–9. https://doi.org/10.1038/s41586-018-0579-z .
doi: 10.1038/s41586-018-0579-z
pubmed: 30305743
pmcid: 6786975
Kurki MI, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613:508–18. https://doi.org/10.1038/s41586-022-05473-8 .
doi: 10.1038/s41586-022-05473-8
pubmed: 36653562
pmcid: 9849126
Ruijsink B, et al. Fully automated, quality-controlled cardiac analysis from CMR: validation and large-scale application to characterize cardiac function. JACC Cardiovasc Imaging. 2020;13:684–95. https://doi.org/10.1016/j.jcmg.2019.05.030 .
doi: 10.1016/j.jcmg.2019.05.030
pubmed: 31326477
Petersen SE, et al. Reference ranges for cardiac structure and function using cardiovascular magnetic resonance (CMR) in Caucasians from the UK Biobank population cohort. J Cardiovasc Magn Reson. 2017;19:18. https://doi.org/10.1186/s12968-017-0327-9 .
doi: 10.1186/s12968-017-0327-9
pubmed: 28178995
pmcid: 5304550
Pinto YM, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37:1850–8. https://doi.org/10.1093/eurheartj/ehv727 .
doi: 10.1093/eurheartj/ehv727
pubmed: 26792875
Villard E, et al. A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy. Eur Heart J. 2011;32:1065–76. https://doi.org/10.1093/eurheartj/ehr105 .
doi: 10.1093/eurheartj/ehr105
pubmed: 21459883
pmcid: 3086901
Stark K, et al. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy. PLoS Genet. 2010;6:e1001167. https://doi.org/10.1371/journal.pgen.1001167 .
doi: 10.1371/journal.pgen.1001167
pubmed: 20975947
pmcid: 2958814
Fagerberg L, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014;13:397–406. https://doi.org/10.1074/mcp.M113.035600 .
doi: 10.1074/mcp.M113.035600
pubmed: 24309898
Carithers LJ, et al. A novel approach to high-quality postmortem tissue procurement: the GTEx project. Biopreserv Biobank. 2015;13:311–9. https://doi.org/10.1089/bio.2015.0032 .
doi: 10.1089/bio.2015.0032
pubmed: 26484571
pmcid: 4675181
Sayers EW, et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 2011;39:D38–51. https://doi.org/10.1093/nar/gkq1172 .
doi: 10.1093/nar/gkq1172
pubmed: 21097890
Ludwiczak J, Winski A, Szczepaniak K, Alva V, Dunin-Horkawicz S. DeepCoil-a fast and accurate prediction of coiled-coil domains in protein sequences. Bioinformatics. 2019;35:2790–5. https://doi.org/10.1093/bioinformatics/bty1062 .
doi: 10.1093/bioinformatics/bty1062
pubmed: 30601942
Verdonschot JAJ, et al. Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences. Eur Heart J. 2021;42:162–74. https://doi.org/10.1093/eurheartj/ehaa841 .
doi: 10.1093/eurheartj/ehaa841
pubmed: 33156912
Pfeufer A, et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet. 2009;41:407–14. https://doi.org/10.1038/ng.362 .
doi: 10.1038/ng.362
pubmed: 19305409
pmcid: 2976045
Newton-Cheh C, et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet. 2009;41:399–406. https://doi.org/10.1038/ng.364 .
doi: 10.1038/ng.364
pubmed: 19305408
pmcid: 2701449
Noseworthy PA, et al. Common genetic variants, QT interval, and sudden cardiac death in a Finnish population-based study. Circ Cardiovasc Genet. 2011;4:305–11. https://doi.org/10.1161/CIRCGENETICS.110.959049 .
doi: 10.1161/CIRCGENETICS.110.959049
pubmed: 21511878
pmcid: 3119024
Roder K, et al. RING finger protein RNF207, a novel regulator of cardiac excitation. J Biol Chem. 2014;289:33730–40. https://doi.org/10.1074/jbc.M114.592295 .
doi: 10.1074/jbc.M114.592295
pubmed: 25281747
pmcid: 4256309
Yuan L, et al. RNF207 exacerbates pathological cardiac hypertrophy via post-translational modification of TAB1. Cardiovasc Res. 2023;119:183–94. https://doi.org/10.1093/cvr/cvac039 .
doi: 10.1093/cvr/cvac039
pubmed: 35352799
DeNicola GF, et al. Mechanism and consequence of the autoactivation of p38alpha mitogen-activated protein kinase promoted by TAB1. Nat Struct Mol Biol. 2013;20:1182–90. https://doi.org/10.1038/nsmb.2668 .
doi: 10.1038/nsmb.2668
pubmed: 24037507
Chu M, et al. Increased cardiac arrhythmogenesis associated with gap junction remodeling with upregulation of RNA-binding protein FXR1. Circulation. 2018;137:605–18. https://doi.org/10.1161/CIRCULATIONAHA.117.028976 .
doi: 10.1161/CIRCULATIONAHA.117.028976
pubmed: 29101288
Ferreira-Cornwell MC, et al. Remodeling the intercalated disc leads to cardiomyopathy in mice misexpressing cadherins in the heart. J Cell Sci. 2002;115:1623–34. https://doi.org/10.1242/jcs.115.8.1623 .
doi: 10.1242/jcs.115.8.1623
pubmed: 11950881
Ito Y, et al. Disorganization of intercalated discs in dilated cardiomyopathy. Sci Rep. 2021;11:11852. https://doi.org/10.1038/s41598-021-90502-1 .
doi: 10.1038/s41598-021-90502-1
pubmed: 34088908
pmcid: 8178322
Heinig M, et al. Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy. Genome Biol. 2017;18:170. https://doi.org/10.1186/s13059-017-1286-z .
doi: 10.1186/s13059-017-1286-z
pubmed: 28903782
pmcid: 5598015
Tripathi S, et al. Unequal allelic expression of wild-type and mutated beta-myosin in familial hypertrophic cardiomyopathy. Basic Res Cardiol. 2011;106:1041–55. https://doi.org/10.1007/s00395-011-0205-9 .
doi: 10.1007/s00395-011-0205-9
pubmed: 21769673
pmcid: 3228959
Montag J, et al. Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy. J Muscle Res Cell Motil. 2017;38:291–302. https://doi.org/10.1007/s10974-017-9486-4 .
doi: 10.1007/s10974-017-9486-4
pubmed: 29101517
pmcid: 5742120
Glazier AA, Thompson A, Day SM. Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy. Pflugers Arch. 2019;471:781–93. https://doi.org/10.1007/s00424-018-2226-9 .
doi: 10.1007/s00424-018-2226-9
pubmed: 30456444
Helms AS, et al. Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. Circ Cardiovasc Genet. 2014;7:434–43. https://doi.org/10.1161/CIRCGENETICS.113.000448 .
doi: 10.1161/CIRCGENETICS.113.000448
pubmed: 25031304
pmcid: 4254656
Parbhudayal RY, et al. Variable cardiac myosin binding protein-C expression in the myofilaments due to MYBPC3 mutations in hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2018;123:59–63. https://doi.org/10.1016/j.yjmcc.2018.08.023 .
doi: 10.1016/j.yjmcc.2018.08.023
pubmed: 30170119
Montag J, Kraft T. Stochastic allelic expression as trigger for contractile imbalance in hypertrophic cardiomyopathy. Biophys Rev. 2020;12:1055–64. https://doi.org/10.1007/s12551-020-00719-z .
doi: 10.1007/s12551-020-00719-z
pubmed: 32661905
pmcid: 7429642
Xing Y, et al. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem. 2003;278:28372–7. https://doi.org/10.1074/jbc.M303521200 .
doi: 10.1074/jbc.M303521200
pubmed: 12766162
Athea Y, et al. AMP-activated protein kinase alpha2 deficiency affects cardiac cardiolipin homeostasis and mitochondrial function. Diabetes. 2007;56:786–94. https://doi.org/10.2337/db06-0187 .
doi: 10.2337/db06-0187
pubmed: 17327449
Qi D, Young LH. AMPK: energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol Metab. 2015;26:422–9. https://doi.org/10.1016/j.tem.2015.05.010 .
doi: 10.1016/j.tem.2015.05.010
pubmed: 26160707
pmcid: 4697457
Zarrinpashneh E, et al. Role of the alpha2-isoform of AMP-activated protein kinase in the metabolic response of the heart to no-flow ischemia. Am J Physiol Heart Circ Physiol. 2006;291:H2875–2883. https://doi.org/10.1152/ajpheart.01032.2005 .
doi: 10.1152/ajpheart.01032.2005
pubmed: 16877552
Pirruccello JP, et al. Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy. Nat Commun. 2020;11:2254. https://doi.org/10.1038/s41467-020-15823-7 .
doi: 10.1038/s41467-020-15823-7
pubmed: 32382064
pmcid: 7206184
Sammani A, et al. UNRAVEL: big data analytics research data platform to improve care of patients with cardiomyopathies using routine electronic health records and standardised biobanking. Neth Heart J. 2019;27:426–34. https://doi.org/10.1007/s12471-019-1288-4 .
doi: 10.1007/s12471-019-1288-4
pubmed: 31134468
pmcid: 6712144